What are the side effects of Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors?

Side Effects of SGLT2 Inhibitors

SGLT2 inhibitors are associated with several important side effects including genital mycotic infections, urinary tract infections, volume depletion, euglycemic diabetic ketoacidosis, and potential risk for lower limb amputations, which require careful monitoring and management. 1

Common Side Effects

Genital Mycotic Infections

• Most frequent adverse event with SGLT2 inhibitors 2
• Higher risk in women and uncircumcised males 3
• Patients with history of genital mycotic infections are more susceptible 4
• Management: Appropriate antifungal treatment and hygiene counseling 2

Urinary Tract Infections (UTIs)

• Occur in approximately 9% of women treated with SGLT2 inhibitors compared to 7% with placebo 1
• Can progress to serious infections including urosepsis and pyelonephritis requiring hospitalization 3, 4
• Management: Standard antibiotic therapy; monitor for signs of infection 3

Volume Depletion

• Caused by osmotic diuresis effect of SGLT2 inhibitors 2, 4
• Symptoms include orthostatic hypotension, dizziness, and dehydration 1
• Higher risk in:
  • Elderly patients
  • Patients on diuretic therapy
  • Patients with renal impairment 2, 4
• Management: Assess volume status before initiation, monitor for signs of depletion, consider reducing dose of concurrent diuretics 2

Serious Side Effects

Euglycemic Diabetic Ketoacidosis

• Rare but serious complication that can occur with normal or only moderately elevated blood glucose 1, 3
• Risk factors:
  • Insulin deficiency
  • Reduced caloric intake
  • Acute illness
  • Surgery
  • Alcohol consumption 2, 4
• Management:
  • Withhold SGLT2 inhibitors during prolonged fasting, surgery, or critical illness 2
  • Discontinue 3-4 days before elective procedures 2
  • Monitor for symptoms (malaise, nausea, vomiting, abdominal pain) 2
  • Immediate medical attention if symptoms develop 2

Lower Limb Amputations

• Increased risk observed primarily with canagliflozin (6.3 vs 3.4 per 1000 patient-years compared to placebo) 2, 3
• Most commonly affects toe and midfoot 3
• Higher risk in patients with:
  • History of prior amputation
  • Peripheral vascular disease
  • Neuropathy
  • Diabetic foot ulcers 3
• Management: Routine preventative foot care, monitor for signs of infection, new pain/tenderness, sores or ulcers 3

Bone Fractures

• Increased risk observed in clinical trials, particularly in older adults 1, 3
• Rate with canagliflozin: 15.4 vs 11.9 per 1000 patient-years compared to placebo 2
• Management: Consider fracture risk when prescribing to older adults 1

Necrotizing Fasciitis of the Perineum (Fournier's Gangrene)

• Very rare but potentially life-threatening condition 1, 3
• Reported in both males and females 3
• Management: Immediate treatment with broad-spectrum antibiotics and surgical debridement if suspected 3

Initial eGFR Decline

• SGLT2 inhibitors typically cause an initial decrease in eGFR of 3-5 mL/min/1.73m² 2
• This "eGFR dip" is generally reversible and kidney function typically returns to baseline in the following weeks 2
• Not an indication to discontinue therapy in most cases 2

Hypoglycemia Risk

• Low risk when used as monotherapy 3, 4
• Increased risk when combined with insulin or insulin secretagogues 3, 4
• Management: Consider reducing dose of insulin or insulin secretagogues when initiating SGLT2 inhibitors 4

Monitoring and Risk Mitigation

1. Before initiating SGLT2 inhibitors:

   • Assess volume status and renal function 4
   • Evaluate risk factors for ketoacidosis, amputation, and fractures 3

2. During treatment:

   • Monitor for genital and urinary symptoms
   • Provide foot care education and regular foot examinations
   • Educate patients on "sick day rules" (when to hold medication during illness)
   • Monitor renal function periodically 2

3. Special considerations:

   • Withhold during prolonged fasting, surgery, or critical illness 2
   • Use cautiously in frail elderly or those prone to orthostasis 1
   • Discontinue 3-4 days before elective procedures 2

Despite these side effects, SGLT2 inhibitors provide significant benefits including cardiovascular risk reduction and renal protection that must be weighed against potential risks when prescribing these medications 2, 1.